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BACKGROUND: Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. METHODS: C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. RESULTS: Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. CONCLUSIONS: These results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.
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Linfócitos T CD4-Positivos/imunologia , Neoplasias da Próstata/imunologia , Células Th17/imunologia , Envelhecimento/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , NF-kappa B/imunologia , Invasividade Neoplásica , Células PC-3 , Neoplasias da Próstata/patologia , Células Th17/patologiaRESUMO
Pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody preparation, has been shown to induce various dermatologic adverse events which may present with delayed onset or even after discontinuation of therapy. We report a 78-year-old female patient with a stage II lung adenocarcinoma treated with pembrolizumab, who developed lichenoid eruptions and multiple cutaneous plaque/nodular eruptions as pseudoepitheliomatous hyperplasia, during and up to 2 months after discontinuation of pembrolizumab therapy. Multiple skin biopsies revealed epidermal hyperplasia with hyperkeratosis, hypergranulosis, diffuse to patchy lichenoid lymphocyte infiltrate with scattered eosinophils and neutrophils, confluent to scant dyskeratosis of the lower epidermis, minimal to overt invagination, and cystic proliferation of squamous epithelium to papillomatosis with hypergranulosis and keratosis. Overall, multiple patterns were present with similarities to lichenoid drug eruption, lichen planus, early invasive squamous cell carcinoma, early keratoacanthoma, and verruca. However, the findings ultimately supported a diagnosis of hypertrophic lichen planus. All the lesions resolved with oral prednisone, hydroxychloroquine, and topical triamcinolone acetonide ointment 0.1%. In summary, our case shows that pembrolizumab can induce lichenoid eruption with pseudoepitheliomatous hyperplasia, and these lesions can clinically and pathologically mimic early invasive squamous cell carcinomas or keratoacanthomas.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Toxidermias/patologia , Líquen Plano/induzido quimicamente , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Diagnóstico Diferencial , Toxidermias/diagnóstico , Feminino , Humanos , Líquen Plano/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
We present a 32-year old woman with a 9-year history of upper facial swelling. A workup by the ophthalmology department led to the diagnosis of Melkersson-Rosenthal syndrome. Re-evaluation in our dermatology clinic confirmed a diagnosis of Morbihan disease. Herein, we review case reports and case series of upper facial swelling in the dermatologic and ophthalmologic literature. Although the two entities share histopathological changes, they tend to have different clinical presentations. Melkersson-Rosenthal syndrome appears to be more likely diagnosed in the ophthalmologic literature when the clinical presentation and histopathology may be more consistent with Morbihan disease. In a patient with upper facial swelling, an absence of orolabial swelling, and lack of facial neuropathy, we argue for a diagnosis of Morbihan disease over Melkersson-Rosenthal syndrome, especially if the patient has a history of rosacea.
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Edema/diagnóstico , Síndrome de Melkersson-Rosenthal/diagnóstico , Adulto , Diagnóstico Diferencial , Edema/patologia , Eritema/diagnóstico , Feminino , Humanos , Rosácea/complicações , Rosácea/diagnóstico , Pele/patologiaRESUMO
OBJECTIVE: In this study, we aimed to examine the association of demographic and socioeconomic factors with cutaneous melanoma that required admission. METHODS: A cross-sectional study utilizing the Nationwide Inpatient Sample database, 2003-2009, was merged with County Health Rankings Data. RESULTS: A total of 2,765 discharge -records were included. Men were more likely to have melanoma in the head, neck, and trunk regions (p < 0.001), while extremities melanoma was more common in women (p < 0.001). Males had a higher risk of lymph node metastasis on presentation (OR 1.54, 95% CI [1.27-1.89]). Blacks and Hispanics were more likely to present with extremities melanoma. Patients with low annual income were more likely to be treated by low-volume surgeons and in hospitals located in high-risk communities (p < 0.05 each). Patients with Medicaid coverage were twice as likely to present with distant metastasis and were more likely to be managed by low-volume surgeons (p < 0.05 each). CONCLUSIONS: The presentation and outcomes of cutaneous melanoma have a distinct pattern of distribution based on patients' characteristics.
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Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/terapia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Melanoma/epidemiologia , Melanoma/terapia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/terapia , Adulto , Estudos Transversais , Bases de Dados Factuais , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Linfática/patologia , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Fatores Socioeconômicos , Estados Unidos/epidemiologia , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Interleukin-17 (IL-17) has been demonstrated to promote formation and growth of hormone-naïve prostate adenocarcinoma in mice. IL-17's role in development of castration-resistant prostate cancer is unknown. In the present study, we investigated IL-17's role in castration-resistant prostate cancer in a mouse model. METHODS: IL-17 receptor C (IL-17RC) deficient mice were interbred with Pten conditional mutant mice to produce RC(+) mice that maintained IL-17RC expression and RC(-) mice that were IL-17RC deficient. Male RC(+) and RC(-) mice were Pten-null and were castrated at 16 weeks of age when invasive prostate cancer had already formed. At 30 weeks of age, all male mice were analyzed for the prostate phenotypes. RESULTS: RC(-) mice displayed prostates that were smaller than RC(+) mice. Approximately 23% of prostatic glands in RC(-) mice, in contrast to 65% of prostatic glands in RC(+) mice, developed invasive adenocarcinomas. Compared to castrate RC(+) mice, castrate RC(-) mouse prostate had lower rates of cellular proliferation and higher rates of apoptosis as well as lower levels of MMP7, YBX1, MTA1, and UBE2C proteins. In addition, castrate RC(-) mouse prostate had less angiogenesis, which was associated with decreased levels of COX-2 and VEGF. Moreover, castrate RC(-) mouse prostate had fewer inflammatory cells including lymphocytes, myeloid-derived suppressor cells, and macrophages. CONCLUSIONS: Taken together, our findings suggest that IL-17 promotes development of invasive prostate adenocarcinomas under castrate conditions, potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment.
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Tolerância Imunológica , Interleucina-17/fisiologia , Neovascularização Patológica/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores de Interleucina-17/fisiologia , Microambiente Tumoral/genética , Animais , Tolerância Imunológica/genética , Interleucina-17/deficiência , Masculino , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Orquiectomia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/imunologia , Receptores de Interleucina-17/deficiênciaRESUMO
Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level.
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BACKGROUND: The role of Th17 cells in prostate cancer (PCa) is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. METHODS: In this study, we aimed to characterize the role of Batf-dependent Th17 cells in PCa by crossbreeding Batf knockout (Batf-/-) mice with mice conditionally mutant for Pten. We found that Batf-/- mice had changes in the morphology of prostate epithelial cells compared to normal mice, and Batf-/- mice deficient in Pten (named Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (named Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of NF-κB signaling. Moreover, Batf- mice showed significantly reduced IL-23/IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared to Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared to control IgG-treated mice. In human prostate tumors, BATF mRNA level was positively correlated with IL23A and IL-23R but not RORC. CONCLUSION: Our novel findings underscore the crucial role of IL-23/IL23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting PCa initiation and progression. This highlights the Batf-IL-23R axis as a promising target for the development of innovative strategies for PCa prevention and treatment.
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Here, we report a case of rubella virus-induced granulomatous dermatitis in a young girl with immunodeficiency caused by DCLRE1C gene mutations. The patient was a 6-year-old girl who presented with multiple erythematous plaques on the face and limbs. Biopsies of the lesions revealed tuberculoid necrotizing granulomas. No pathogens could be identified on extensive special stains, tissue cultures, or PCR-based microbiology assays. Metagenomic next-generation sequencing analysis revealed the rubella virus. Underlying atypical severe combined immunodeficiency was recognized based on the patient's history of repetitive infections since birth, low T-cell, B-cell, and NK cell counts, and abnormal immunoglobulins and complements. Whole-exome sequencing revealed the genetic abnormality of the atypical severe combined immunodeficiency (SCID), and compound heterozygous mutations of the DCLRE1C gene were detected. This report highlights the diagnostic values of metagenomic next-generation sequencing in identifying rare pathogens causing cutaneous granulomas in patients with atypical SCID.
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Patients with psoriasis tend to develop skin cancer, and the hyperproliferation of the epidermis is a histopathological hallmark of both psoriasis and cutaneous squamous cell carcinoma (SCC), indicating that they may share pathogenic mechanisms. Interleukin-17 (IL17) stimulates the proliferation of the epidermis, leading to psoriasis. Overexpression of Polo-like kinase 4 (PLK4), which controls centriole duplication, has been identified in SCC, which also shows the hyperproliferation of keratinocytes. To investigate the cooperation between IL17 signaling and centriole duplication in epidermal proliferation, we established psoriasis and skin papilloma models in wild type (WT), IL17 receptor A (T779A) knockin (Il17ra(T779A)-KI), and IL17 receptor C knockout (Il17rc-KO) mouse strains. Bioinformatics, Western blot, immunohistochemical staining, colony formation, and real-time PCR were used to determine the effect of IL17 signaling and centrinone on epithelial proliferation. In the psoriasis model, compared to WT and Il17ra(T779A)-KI, Il17rc-KO dramatically suppressed epidermal thickening. The proliferation of keratinocytes significantly decreased in this order from WT to Il17ra(T779A)-KI and Il17rc-KO mice. In the skin papilloma model, Il17ra(T779A)-KI significantly decreased tumor burden compared to the WT, while Il17rc-KO abolished papilloma development. However, centrinone, a selective inhibitor of PLK4, did not affect skin lesion formation in either model. Our data demonstrated that Il17ra(T779A)-KI and Il17rc-KO prevent the development of psoriasis and tumorigenesis in the skin, while the topical administration of centrinone does not have any effect.
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Several cases of pigmented mammary Paget's disease (PMPD) mimicking cutaneous malignant melanoma have been reported. In these cases, the tumor cells are colonized by melanocytes, particularly with the presence of a population of melanocytes staining for HMB-45 and S100. Here, we report a case of mammary Paget disease (MPD) which was misdiagnosed as melanoma in situ due to the interpretation of the staining of melanocytic markers S-100, Melan-A, and HMB-45. The tumor cells strongly expressed CK7 and GATA3, and a dual-labeling showed negative PHH3 labeling for the melanocytes. Pathologists need to be aware of the caveat of colonization of melanocytes in Paget disease.
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Cutaneous mercury (Hg) granuloma is a rare disorder caused by the traumatic introduction of elemental Hg into skin or soft tissue. Typically, cutaneous elemental Hg deposits cause limited systemic effects. Prominent systemic toxicity may, however, occasionally occur. Herein we report a case of cutaneous Hg granuloma resulting in chronic painful local wounds and systemic toxicity in the form of abdominal pain, visual disturbances, and psychiatric abnormalities. The related literature also is reviewed.
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Granuloma de Corpo Estranho/etiologia , Intoxicação por Mercúrio/patologia , Dermatopatias/induzido quimicamente , Adulto , Feminino , Infecções por HIV/terapia , Honduras , Humanos , Injeções Subcutâneas , Mercúrio/administração & dosagem , Mercúrio/toxicidadeRESUMO
Localized cartilage lesions in early osteoarthritis and acute joint injuries are usually treated surgically to restore function and relieve pain. However, a persistent clinical challenge remains in how to repair the cartilage lesions. We expressed doublecortin (DCX) in human adipose-derived stromal/stem cells (hASCs) and engineered hASCs into cartilage tissues using an in vitro 96-well pellet culture system. The cartilage tissue constructs with and without DCX expression were implanted in the knee cartilage defects of rabbits (n = 42) and monkeys (n = 12). Cohorts of animals were euthanized at 6, 12, and 24 months after surgery to evaluate the cartilage repair outcomes. We found that DCX expression in hASCs increased expression of growth differentiation factor 5 (GDF5) and matrilin 2 in the engineered cartilage tissues. The cartilage tissues with DCX expression significantly enhanced cartilage repair as assessed macroscopically and histologically at 6, 12, and 24 months after implantation in the rabbits and 24 months after implantation in the monkeys, compared to the cartilage tissues without DCX expression. These findings suggest that hASCs expressing DCX may be engineered into cartilage tissues that can be used to treat localized cartilage lesions.
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Prostate cancer (PCa) is associated with advanced age, but how age contributes to prostate carcinogenesis remains unknown. The prostate-specific Pten conditional knockout mouse model closely imitates human PCa initiation and progression. To better understand how age impacts PCa in an experimental model, we have generated a spatially and temporally controlled Pten-null PCa murine model at different ages (aged vs. non-aged) of adult mice. Here, we present a protocol to inject the Cre-expressing adenovirus with luciferin tag, intraductally, into the prostate anterior lobes of Pten-floxed mice; Pten-loss will be triggered post-Cre expression at different ages. In vivo imaging of luciferin signal following viral infection confirmed successful delivery of the virus and Cre activity. Immunohistochemical staining confirmed prostate epithelial-specific expression of Cre recombinase and the loss of Pten and activation of P-Akt, P-S6, and P-4E-BP1. The Cre-expression, Pten ablation, and activated PI3K/AKT/mTOR pathways were limited to the prostate epithelium. All mice developed prostatic epithelial hyperplasia within 4 weeks after Pten ablation and prostatic intraepithelial neoplasia (PIN) within 8 weeks post-Pten ablation. Some PINs had progressed to invasive adenocarcinoma at 8-16 weeks post-Pten ablation. Aged mice exhibited significantly accelerated PI3K/AKT/mTOR signaling and increased PCa onset and progression compared to young mice. The viral infection success rate is â¼80%. This model will be beneficial for investigations of cancer-related to aging.
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The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.
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Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Indóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Fenotiazinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Fenotiazinas/química , Fenotiazinas/farmacocinética , Fenotiazinas/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The skin is the outer layer of protection against the environment. The development and formation of the skin is regulated by several genetic cascades including the bone morphogenetic protein (BMP) signaling pathway, which has been suggested to play an important role during embryonic organ development. Several skin defects and diseases are caused by genetic mutations or disorders. Ichthyosis is a common genetic skin disorder characterized by dry scaly skin. Loss-of-function mutations in the filaggrin (FLG) gene have been identified as the cause of the ichthyosis vulgaris (IV) phenotype; however, the direct regulation of filaggrin expression in vivo is unknown. We present evidence that BMP signaling regulates filaggrin expression in the epidermis. Mice expressing a constitutively active form of BMP-receptor-IB in the developing epidermis exhibit a phenotype resembling IV in humans, including dry flaky skin, compact hyperkeratosis, and an attenuated granular layer associated with a significantly downregulated expression of filaggrin. Regulation of filaggrin expression by BMP signaling has been further confirmed by the application of exogenous BMP2 in skin explants and by a transgenic model overexpressing Noggin in the epidermis. Our results demonstrate that aberrant BMP signaling in the epidermis causes overproliferation and hyperkeratinization, leading to an IV-like skin disease.
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Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Epiderme/metabolismo , Ictiose Vulgar , Animais , Western Blotting , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Proteínas de Transporte/genética , Diferenciação Celular , Proliferação de Células , Epiderme/embriologia , Epiderme/patologia , Proteínas Filagrinas , Imunofluorescência , Regulação da Expressão Gênica , Genótipo , Ictiose Vulgar/genética , Ictiose Vulgar/metabolismo , Ictiose Vulgar/patologia , Proteínas de Filamentos Intermediários/genética , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , Reação em Cadeia da Polimerase , Transdução de SinaisRESUMO
Human orf, also called ecthyma contagiosum, is a zoonotic infection that causes self-resolving skin lesions after contact with infected livestock. We present the case of a 45-year-old Moroccan-born man who developed multiple painful erythematous, violaceous plaques on his hands after butchering a sheep to celebrate the Muslim holiday Eid al-Adha. The diagnosis of orf virus infection was established based on exposure history, histopathology, and classic skin lesions. Although orf virus infection is traditionally seen in individuals with frequent animal contact such as farmers and veterinarians, clinicians evaluating suspicious lesions in patients without occupational risk factors should consider additional cultural practices that may expose the patient to orf virus.
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Backgroud: Recently, atypical persistent skin eruptions (APSEs) have been documented as a new manifestation of adult-onset Still's disease (AOSD), with a unique pathological feature of necrotic keratinocytes in the upper third of the epidermis, but the mechanism has not been elucidated. The aim of this study was to explore the potential mechanism of the unique pathological phenomenon of APSEs.Methods: Clinical and pathological data from 26 AOSD patients with APSEs and 6 with evanescent skin eruptions (ESEs) were reviewed. Fourteen APSE biopsies and 6 ESE biopsies were selected for multi-spectrum immunohistochemistry with 5 disease controls and 5 healthy controls.Results: The unique pathological manifestation was present in all APSE patients but was hardly found in ESE patients. There were more CD4 + T-cells infiltrated in the dermis of APSEs than in the dermis of ESEs. IL-1ß and IFN-γ were specifically expressed in the upper third of the epidermis and were juxtaposed to the loci of the necrotic keratinocytes.Conclusion: Our findings showed important cellular and molecular derangements related to the APSE-specific pathological phenomena and helped to understand the pathogenesis of dyskeratosis in the epidermis. The findings could also pave a way to explore an effective intervention to this potentially life-threatening disorder.
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Regulação da Expressão Gênica/imunologia , Interferon gama , Interleucina-1beta , Queratinócitos , Doença de Still de Início Tardio , Adolescente , Adulto , Idoso , Feminino , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Doença de Still de Início Tardio/imunologia , Doença de Still de Início Tardio/metabolismo , Doença de Still de Início Tardio/patologiaRESUMO
Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca(2+) channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca(2+) channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca(2+) channels are not expressed in epithelial cells, selective T-type Ca(2+) channel blockers may be useful in the treatment of certain types of cancers.